Many medicinal reagents for the treatment of cancer originate from natural resources. To obtain sufficient quantities of these molecules and to improve their biological profile it is often necessary to produce these compounds synthetically. Monanchocidin, a member of the crambescidin family, is an attractive target for synthesis due to its complex structure and promising inhibition of cancer cell growth. An innovative strategy is proposed to address the synthesis of this molecule employing palladium catalyzed asymmetric allylic alkylation (AAA) and a novel hydroguanidination/cyclization sequence. The objective of this proposal is to develop a concise enantioselective synthesis of monanchocidin using newly developed reactions. We hypothesize that the pentacyclic guanidine can be rapidly assembled stereoselectively by developing a transition metal catalyzed hydroguanidination reaction. The specific aims of this project are; (1) to utilize palladium-catalyzed asymmetric allylic alkylation to construct the pyrolidine core of monanchocidin and other crambescidin family members, (2) develop and implement a novel transition-metal catalyzed hydroguanidination-spirocyclization method to assemble the pentacyclic guanidine, (3) develop an expedient synthetic route to access the fatty acid side chain in monanchocidin, and (4) develop a fragment coupling strategy that provides an efficient and modular route toward the first total synthesis of monanchocidin. The proposed research will be executed in an efficient manner by synthesizing key fragments enantioselectively and coupling them to the pyrolidine core of monanchocidin; assembled via palladium catalyzed asymmetric allylic alkylation (AAA). A novel method for construction of the pentacyclic guanidine of monanchocidin will be developed using a transition metal catalyzed hydroguanidination. An examination of transition metals typically used in hydroamination reactions will be conducted and the most efficient of these will be further optimized and employed in the proposed synthesis. PUBLIC HEALTH RELEVANCE: During the last half century, many of the current treatments for various types of cancer have been inspired by nature. Obtaining sufficient quantities of these compounds for proper testing remains a major limitation for their use as chemotherapies. Synthetic chemistry is one resource that enables the production of these molecules and the flexibility of this approach typically enables the synthesis of analogs that in many cases show improved activities or fewer side effects critical for their development as medicinal reagents to improve public health.